Vascular plaque causes several medical conditions, including but not limited to, coronary artery disease, carotid artery disease, and peripheral artery disease.
Atherogenesis is the developmental process of atheromatous plaques. The build-up of an atheromatous plaque is a slow process, developed over a period of several years through a complex series of cellular events occurring within the arterial wall, and in response to a variety of local vascular circulating factors. Atheromatous plaques form in the arterial tunica intima, a region of the vessel wall located between the endothelium and the tunica media. The bulk of these lesions are made of excess fat, collagen, and elastin. At first, as the plaques grow, only wall thickening occurs without any significant narrowing. Stenosis is a late event, which may never occur and is often the result of repeated plaque rupture and healing responses, not just the atherosclerotic process by itself. Such vascular stenoses are alternatively referred to as vascular lesions.
Intracellular microcalcifications form within vascular smooth muscle cells of the surrounding muscular layer, specifically in the muscle cells adjacent to the atheromas. In time, as cells die, this leads to extracellular calcium deposits between the muscular wall and outer portion of the atheromatous plaques. The outer, older portions of the plaque become more calcific, less metabolically active and more physically rigid over time.
Two plaque types can be distinguished:
The fibro-lipid (fibro-fatty) plaque is characterized by an accumulation of lipid-laden cells underneath the intima of the arteries, typically without narrowing the lumen due to compensatory expansion of the bounding muscular layer of the artery wall. Beneath the endothelium there is a “fibrous cap” covering the atheromatous “core” of the plaque. The core consists of lipid-laden cells (macrophages and smooth muscle cells) with elevated tissue cholesterol and cholesterol ester content, fibrin, proteoglycans, collagen, elastin, and cellular debris. In advanced plaques, the central core of the plaque usually contains extracellular cholesterol deposits (released from dead cells), which form areas of cholesterol crystals with empty, needle-like clefts. At the periphery of the plaque are younger “foamy” cells and capillaries. These type of plaques are sometimes referred to as vulnerable plaques, and usually produce the most damage to the individual when they rupture, often leading to fatal myocardial infarction when present within the coronary arteries.
The fibrous plaque is also localized under the intima, within the wall of the artery resulting in thickening and expansion of the wall and, sometimes, spotty localized narrowing of the lumen with some atrophy of the muscular layer. The fibrous plaque contains collagen fibers (eosinophilic), precipitates of calcium (hematoxylinophilic) and, rarely, lipid-laden cells.
Atheromas within the vessel wall are soft and fragile with little elasticity. In addition, the calcification deposits between the outer portion of the atheroma and the muscular wall of the blood vessel, as they progress, lead to a loss of elasticity and stiffening of the blood vessel as a whole.
The calcification deposits, after they have become sufficiently advanced, are partially visible on coronary artery computed tomography or electron beam tomography (EBT) as rings of increased radiographic density, forming halos around the outer edges of the atheromatous plaques, within the artery wall. On CT, >130 units on the Hounsfield scale (some argue for 90 units) has been the radiographic density usually accepted as clearly representing tissue calcification within arteries. A carotid intima-media thickness scan (CIMT can be measured by B-mode ultrasonography) measurement has been recommended by the American Heart Association as the most useful method to identify atherosclerosis.
Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are the current most sensitive intravascular methods for detecting and measuring more advanced atheroma within living individuals. However, these imaging systems are seldom used for assessment of atheroma in view of their cost, which is not reimbursed in many medical environments, as well as invasive risks.
Angiography, since the 1960s, has been the traditional way of evaluating atheroma. However, angiography is only motion or still images of dye mixed with the blood within the arterial lumen and do not directly visualize atheroma. Rather, the wall of arteries, including atheroma with the arterial wall, generally remain invisible, with only limited shadows which define their contoured boundaries based upon x-ray absorption. The limited exception to this rule is that with very advanced atheroma, with extensive calcification within the wall, a halo-like ring of radiodensity can be seen in older patient, especially when arterial lumens are visualized end-on. On cine-floro, cardiologists and radiologists typically look for these calcification shadows to recognize arteries before they inject any contrast agent during angiograms.
Interventional vascular procedures, such as percutaneous transluminal angioplasty (PTA) for peripheral vascular disease and percutaneous transluminal coronary angioplasty (PTCA) for coronary artery disease, are typically performed using an inflatable balloon dilatation catheter to restore increased luminal diameter at the vascular lesion. During a typical PTA procedure, the dilatation catheter is positioned within the blood vessel at the location of the narrowing caused by the lesion, and the balloon is expanded with inflation fluid to dilate the vessel lumen. Following the dilatation, it is common to introduce a second balloon catheter which carries and deploys an expandable metal stent which serves to maintain vessel patency.
However, patients with calcified plaque present a much more difficult challenge for intervention. Indeed, presentation of diffuse, calcified vascular plaque within coronary arteries is often one of the most critical exclusion criteria for PTCA patient candidates, and these patients are instead required to receive invasive coronary artery bypass graft (CABG) surgery to alleviate the coronary blood flow deficiencies. On the other hand, patients presenting diffuse, calcified vascular plaque in their peripheral arteries and veins may still be eligible for PTA vascular intervention, but these patients typically require a preliminary interventional procedure involving plaque removal, such as atherectomy catheters.
In the event that an atherectomy procedure is required, the interventional physician must first deploy an embolic protection device (EPD) within the vessel being treated at a location which is distal (i.e., downstream relative to blood flow) to the atherectomy treatment site. Despite the adjunctive use of such an EPD, plaque particulates which are dislodged by the atherectomy device can occasionally escape the EPD and travel downstream within the vasculature causing a stroke, heart attack or otherwise permanently compromised distal vascular blood flow. In any event, the use of atherectomy devices produces substantial trauma to the blood vessel, and can produce serious complications such as thrombosis, as well as poor vascular healing response leading to premature restenosis.
To the extent that the interventional physician performs a PTA procedure within a blood vessel containing a lesion formed of calcified plaque, dilating such a lesion is more likely to produce increased vascular damage to the vascular tissue, such as microdissections of the vascular tissue.
It is accordingly a primary object of the invention to provide a compound, in the form of a composition, to be administered to a patient in need thereof, wherein the compound will disrupt the crystalline structure of the calcified plaque resulting in at least one of a softening of the plaque, and an increase in lumen diameter.